Physiochemical factors profoundly influence the metabolic status of the eye, yet most are poorly defined. This application involves investigation into several systemic factors that may alter retinal and cerebral hemodynamics, the objective being first to define the normal regulatory response, so that regulatory dysfunctions that exist in diabetic or glaucomatous eyes can be characterized. The first specific aim is to define the independent ocular effects of variations in systemic O2, CO2, and exercise level. Total retinal blood flow, mean retinal capillary flow velocity, the inhOmogeneity of retinal capillary flow rates, the perifoveal intercapillary distance, and the size of the foveal avascular zone will be measured with a scanning laser ophthalmoscope. Intraocular pressure, using Goldmann applanation tonometry, along with testing of contrast sensitivity and visual acuity, will further define the ocular response. Carotid and ophthalmic arterial blood flow, measured using color doppler imaging, will provide the second specific aim of defining the relationship of ocular hemodynamics to regional perfusion. The third goal of the proposed research is to determine the differences in retinal and regional circulatory regulatory response to O2, CO2, and exercise among diabetic patients without retinopathy, patients with diabetes and ophthalmoscopic evidence of retinopathy, and age-matched healthy persons. A fourth aim is to define how varying levels of blood glucose, in age-matched control as compared with diabetic patients, affect retinal and cerebral regulatory responses. Retinal and cerebral circulatory regulation in healthy as compared with glaucomatous eyes will comprise the fifth specific aim. A subgroup of persons with ocular hypertension but without glaucoma will be included. Both hypocapnia and moderate exercise acutely lower intraocular pressure: it is hypothesized that these stimuli may significantly enhance retinal flow in ocular hypertensives and glaucoma patients. The final specific aim is to define how drugs (a non-selective beta-adrenergic blocker, a selective beta1-adrenergic blocker, and a topical carbonic anhydrase inhibitor) that are known to lower intraocular pressure, affect retinal, ophthalmic, and cerebral flow regulation in healthy eyes, both young and old. These proposed studies will be the first to simultaneously investigate retinal, ophthalmic, and cerebral blood flow regulation. Placing the retinal circulation in its regional context will advance understanding of the pathophysiology of diabetic retinopathy and glaucoma, and of the mechanisms by which topical ocular hypotensive drugs exert their actions. This understanding may expedite development of new vasoactive compounds to treat eye diseases.